Gordis L, Markowitz M, Lillienfeld AM. Studies in the epidemiology and preventability of rheumatic fever IV:
a quantitative determination of compliance in children on oral penicillin
prophylaxis. Pediatrics.1969;43:173-182.

Low adherence to prescribed medical regimens is a ubiquitous problem.
Typical adherence rates are about 50% for medications and are much lower for
lifestyle prescriptions and other more behaviorally demanding regimens. In
addition, many patients with medical problems do not seek care or drop out
of care prematurely. Although accurate measures of low adherence are lacking
for many regimens, simple measures, such as directly asking patients and watching
for appointment nonattendance and treatment nonresponse, will detect most
problems. For short-term regimens (≤2 weeks), adherence to medications
is readily achieved by giving clear instructions. On the other hand, improving
adherence to long-term regimens requires combinations of information about
the regimen, counseling about the importance of adherence and how to organize
medication taking, reminders about appointments and adherence, rewards and
recognition for the patient's efforts to follow the regimen, and enlisting
social support from family and friends. Successful interventions for long-term
regimens are all labor-intensive but ultimately can be cost-effective.

Medical research during the past few decades has produced efficacious
treatments for many health care disorders and, increasingly, these treatments
can be self-administered. Unfortunately, low adherence can undermine the effectiveness
of care at many steps in the process.1 For
example, 49% of patients who demonstrated elevated blood pressure on community
screening failed to follow through with a referral for follow-up assessment.
Of those who enter the medical care system, more than a third may drop out,
especially during the first few months. While in care, the average consumption
of medication has been found to be about 50%, with a very wide range from
none to substantially more than 100%. Compliance with instructions to lose
weight or stop smoking is substantially lower, with long-term success rates
less than 10%.2

One of the important difficulties in managing low adherence is lack
of accurate and affordable measures. Clinicians must frequently rely on their
own judgment but unfortunately demonstrate no better than chance accuracy
in predicting the adherence of their patients,3 even
among patients for whom they feel confident about their predictions.4 A pragmatic approach to measuring adherence is presented
in Box 1. Based on a systematic review of studies
adherence measures,3 asking nonresponders about
their adherence will detect more than 50% of those with low adherence, with
a specificity of 87%. Even when patients indicate that they have not taken
all their medications as prescribed, their estimates usually substantially
overestimate their actual adherence. Thus, the key validated question is "Have
you missed any pills in the past week?" and any indication of having missed
1 or more pills signals a problem with low adherence. Overestimation of adherence
by patients is difficult to study and is presently poorly documented. Reasons
for overestimation could include difficulty recalling the details of medication
taking, attempting to please practitioners or to avoid confrontation, or a
combination of these factors. Other practical measures to assess adherence
include watching for those who do not respond to increments in treatment intensity
and patients who fail to attend appointments.

More objective measures of compliance can also be of use when available.
For example, drug levels in body fluids (blood, saliva, urine) can help in
assessing patient compliance (eg, serum digoxin levels and levels of antiepilepsy
medications), but these measurements are affected by dose and timing and can
be misleading if the patient takes the dose only just before clinic visits.
Furthermore, drug levels are often not routinely available for most medications.
Pharmacy records can also be helpful in a health care system that includes
integrated pharmacy services, provided that patients use only the pharmacy
where monitoring occurs and do not stockpile drugs or give them to others.
Finally, medication monitors can provide both frequency and patterns of use
but to date have been too expensive and cumbersome for routine practice.

Several ethical issues must be addressed when considering and attempting
to improve patient adherence.5,6 First,
before adherence becomes a legitimate concern, the clinical diagnosis must
be correctly established. Second, the treatment being prescribed must be of
known efficacy for this diagnosis and appropriate for the patient's circumstances.
Third, methods for helping the patient to follow the treatment must be of
established effectiveness (or otherwise will be a waste of resources, at best).
Fourth, the patient's right to refuse treatment must be respected at all times.
Attempts to coerce the patient to adhere by, for example, threatening dire
outcomes from poor control of the disorder, are doubly unethical because negative
reinforcement has not been shown to work any better than positive reinforcement
and because some patients with high anxiety levels simply withdraw from care
when threatened.7

Our recommendations for assisting patients to follow prescribed medical
regimens are based on the best evidence available from randomized controlled
trials of adherence interventions.8 In the
Scientific Review,8 so few studies of short
courses of treatment reported on clinical outcomes that randomized trials
were added in which only adherence was measured.9- 11 Interventions
are summarized in
Box 2 and Box 3 and we discuss their applications in the context of questions that
commonly arise in practice about adherence.

Box 2. Increasing Adherence With Short-term Treatments*

Counseling about the importance of adherence
Written instructions about taking medicines

Reminder packaging (eg, calendar packs, dosettes)

*Based on references 8-11.

Box 3. Increasing Adherence With Long-term Treatments*

Combinations of
Instruction and instructional materials
Simplifying the regimen (eg, less frequent dosing, controlled release dosage forms)
Counseling
about the regimen
Support group sessions
Reminders (manual and computer) for medications and appointments
Cuing medications to daily events
Reinforcement and rewards (eg, explicitly acknowledging the patient's efforts to adhere)
Self-monitoring with regular physician review and reinforcement
Involving family members and significant others

Is This Patient Following the Treatment as Prescribed? If Not, What
Can I Do About It?

A 57-year-old obese, white, male smoker with type 2 diabetes and mild
proteinuria, dyslipidemia, hypertension, and ischemic heart disease (prior
myocardial infarction) attends a routine follow-up. He complains of some urinary
frequency, including nocturia 2 to 3 times a night, but otherwise feels well.
He provides a record of 11 self-assessed blood glucose readings in the past
month, with a range of 90 to 216 mg/dL (5-12 mmol/L).

His current regimen consists of a calorie-fat-salt reduced diet, regular
exercise, self-monitoring of blood glucose and blood pressure, 50 mg of atenolol
twice daily, 25 mg of hydrochlorothiazide daily, 20 mg of simvastatin at night,
10 mg of glyburide twice daily, and a request that he stop smoking. He has
not been able to lose weight despite attempting to follow a calorie-restricted
diet and walking about half a mile once or twice a week. When asked whether
he had missed taking any of his medications during the past week, he indicated
that he "might have missed 1 or 2 on Saturday night when he was out at a movie."

On examination, he weighs 109 kg, has a blood pressure of 172/98 mm
Hg, scattered dot hemorrhages on funduscopy, and decreased sensation in his
feet on monofilament testing. Incidental inquiry during the examination revealed
that he had started drinking cranberry juice, 2 to 3 L per day, after seeing
an infomercial claiming that it is a vascular cleanser with antioxidants that
can prevent heart disease. The patient's blood glucose meter is checked at
the visit and found to be giving falsely low readings. Recent tests include
hemoglobin A1c of 12.3%, total cholesterol of 264 mg/dL (6.84 mmol/L)
and triglycerides of 486 mg/dL (5.5 mmol/L), serum creatinine of 1.4 mg/dL
(124 µmol/L), and a urinary microalbumin/creatinine ratio of 61.9 mg/g
(7 mg/mmol) (normal <26.8 mg/g [<3 mg/mmol]).

This patient's difficulties include low adherence to his prescribed
diet, exercise regimen, antismoking advice, and medications. Furthermore,
he will need additional treatments for the problems detected on examination,
namely retinopathy and nephropathy, thereby, adding to his adherence burden.
Indications of his low adherence include his persistently high weight, self-report
of little regular exercise, admission of missing pills, a discrepancy between
his self-reported blood glucose and the hemoglobin A1c, as well
as infrequent self-reported glucose monitoring. It is essential to recognize
that a self-report indicating missing any medications is consistent with a
medication adherence rate of less than 60%.3

It is important to recognize that he has been prescribed a very complicated
regimen of diet, exercise, smoking cessation, and medications, including 8
pills per day. Although this type of regimen is both consistent with practice
guidelines and commonplace to prescribe, few are able to follow such a regimen
closely for any length of time. The patient has also been treating himself
with cranberry juice, which has a substantial glucose content that he indicates
he was not aware of (despite having been given dietary advice about checking
the nature and calorie content of all foods ingested).

The first step is to eliminate the factors that are aggravating his
diabetes. The cranberry juice should be stopped if he will agree and the glyburide,
which is associated with weight gain, should be switched to metformin, which
is not.12 Ramipril, an angiotensin-converting
enzyme inhibitor that reduces cardiovascular risk and incipient nephropathy,
and also lowers blood pressure and blood glucose,13 should
be substituted for the thiazide diuretic, which can increase insulin resistance.
As a matter of priority, diet, exercise, and smoking cessation can be deferred
until the blood glucose is brought under control. Managing the dyslipidemia
may also be deferred for now; the lipids may come under control as the blood
glucose improves. Finally, the patient's blood glucose meter should be replaced.
Because so many changes are being made to the patient's regimen, written instructions
of what to start and what to stop should be provided. The patient should be
requested to take all medications as prescribed, to the best of his ability,
during the next 2 weeks, and a follow-up visit should be scheduled at that
time for a review and reassessment.

This approach is insufficient compared with the guideline of making
diet and exercise the foundation for diabetes control.14,15 Rather,
it follows the evidence from observational studies of nonadherence that show
that the complexity and behavioral demand of the regimen are strong determinants
of low adherence2 and that simplification of
the regimen is often needed to achieve adequate adherence. Furthermore, it
follows the evidence for improving adherence both for short periods
(Box 2),8- 11 namely
giving clear instructions about regimens, and for longer periods
(Box 3),8 namely reinforcing the importance of high adherence,
negotiating priorities with the patient, and providing an opportunity for
follow-up reinforcement sooner rather than later. Once the medication regimen
is addressed, fine-tuning can begin on the other aspects of the regimen. If
necessary, follow-up can be shared with nurses, specialists, pharmacists,
or even family members, if the patient and his significant others are willing.
As a matter of urgency, an eye examination by an ophthalmologist should also
be arranged.

This patient's case also illustrates 2 problems that are not due to
low adherence with prescribed treatments but that can still adversely affect
management. First, the patient has taken on a nonprescribed alternative treatment,
copious amounts of cranberry juice, in the unfounded belief that this will
reduce his cardiovascular risk. In fact, the sugar in the cranberry juice
will materially affect his blood glucose and weight control. Second, home
monitoring (of blood pressure and blood glucose in this case) can be a useful
part of an effective adherence intervention but also can be inaccurate and
misleading through faulty equipment, faulty technique, and falsified reports.

Has This Patient Dropped Out of Care?

A 47-year-old woman with hypertension misses her scheduled appointment
without canceling it. Previously, she has shown regular attendance but has
complained from time to time about adverse effects from her medication.

In the midst of a busy clinic, this event can easily go unnoticed or
may even be seen as transient relief from the demands of the day. If noticed,
one can speculate that the patient forgot the appointment, had other commitments,
does not feel that a follow-up is needed at this time, has decided to discontinue
care, or is pursuing a competitor's practice. Missing appointments is correlated
with lower adherence rates to prescribed regimens16,17 and
is the first signal of dropping out of care entirely, the most severe form
of nonadherence, and thus should be followed up by the clinic if ongoing care
is clinically indicated.

A systematic review18 indicates that
this problem is relatively easily overcome by appointment reminders by letter
or telephone, by contracting with patients to keep appointments, and by contacting
patients immediately if appointments are missed. Calling patients who miss
appointments is logically the most important method of helping patients adhere
to prescribed regimens, because reminding or recalling patients is effective
and relatively inexpensive13 and dropping out
of care results in zero adherence to prescribed medications. However, the
effect on medication adherence of keeping patients from dropping out of care
has not been isolated from other interventions in a controlled trial.

Conclusions

To reap the benefits of modern medical therapies, better, more effective,
and more efficient interventions for helping people to follow regimens are
needed. For long-term self-administered medications, the methods of helping
patients adhere to regimens that have been tested and found successful to
date typically have been complex and labor-intensive, and have modest effects
at best on adherence and inconsistent effects on clinical outcomes. Perhaps
researchers and manufacturers should rethink the current methods of product
development that typically result in pills that must be taken several times
per day for as long as the medical condition persists.

Nevertheless, a combination of keeping the regimen as simple as possible,
negotiating priorities with the patient, providing clear instructions, reminding
patients about appointments, monitoring adherence with treatments and appointments,
calling patients who have missed appointments for needed follow-up care, and
reinforcing the importance of high adherence at each visit will provide practical
and effective help for many patients to follow their regimens. If resources
permit, one can add counseling and continuing support from other health care
professionals. If needed, and with the patient's permission, the help of family
members and significant others can be sought. In our view, success in reaching
treatment goals, rather than the extent to which the regimen matches recommended
care guidelines, should be the arbiter of whether the approach is helping
the individual patient.

Of importance, detriment also can arise from interventions that enhance
adherence. First, the regimen can be oversimplified. For example, Girvin et
al19 compared 20 mg of enalapril once daily
with 10 mg of enalapril twice daily for high blood pressure and found that
overall medication adherence was improved, but blood pressure was slightly
better controlled on the twice daily group, presumably because the percentage
of days when no doses were taken was also significantly higher in the once
daily regimen. Second, patient instruction does not have a lasting effect
on long-term adherence8 and can have adverse
effects especially if it emphasizes the adverse consequences on disease outcomes
of failing to adhere.7 Finally, attempting
to enhance adherence can be expensive, especially in personnel costs. Fortunately,
at least 1 trial20 has shown that adherence
intervention was cost-effective.

Gordis L, Markowitz M, Lillienfeld AM. Studies in the epidemiology and preventability of rheumatic fever IV:
a quantitative determination of compliance in children on oral penicillin
prophylaxis. Pediatrics.1969;43:173-182.